CN1473042A - Medical compositions - Google Patents
Medical compositions Download PDFInfo
- Publication number
- CN1473042A CN1473042A CNA018184723A CN01818472A CN1473042A CN 1473042 A CN1473042 A CN 1473042A CN A018184723 A CNA018184723 A CN A018184723A CN 01818472 A CN01818472 A CN 01818472A CN 1473042 A CN1473042 A CN 1473042A
- Authority
- CN
- China
- Prior art keywords
- hmg
- pharmaceutical composition
- coa reductase
- reductase inhibitor
- pravastatin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title abstract description 8
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims abstract description 57
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims description 54
- -1 amide sulfate Chemical class 0.000 claims description 37
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- 229960002965 pravastatin Drugs 0.000 claims description 36
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims description 36
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 29
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 29
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Abstract
Medicinal compositions for administering N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide or its pharmacologically acceptable salt and an HMG-CoA reductase inhibitor either at the same time or separately after a definite period of time.
Description
Technical field
The present invention relates to be used for give simultaneously or give respectively blanking time N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2, the pharmaceutical composition of 2-dimethyl propylene amide or its officinal salt and 3-hydroxy-3-methylglutaric acid list acyl CoA (being designated hereinafter simply as HMG-CoA) reductase inhibitor.
In addition, the invention still further relates to the method for prevention or treatment arteriosclerosis or vitiligoidea (particularly arteriosclerosis), comprise (1-octyl group-5-carboxymethyl-4 with N-, 6-dimethyl indoline-7-yl)-2, the pharmacologically effective dose of 2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor gives or gives respectively blanking time Homoiotherm (particularly people) simultaneously.
Background technology
Along with Occidentalizing and the aging of population etc. of diet, medicated porridge sample arteriosclerosis constantly increases.Medicated porridge sample arteriosclerosis is the main cause of myocardial infarction and cerebral infarction, cerebral hemorrhage etc., is therefore seeking its effective prevention method and Therapeutic Method always.As causing the arteriosclerotic risk factor of medicated porridge sample, except that hyperlipemia (particularly hypercholesterolemia disorders of blood), can also exemplify hypertension, based on the abnormal carbohydrate metabolism of insulin resistance.In addition, these risk factors are more as the situation of complication (syndrome X) morbidity, think the cause of disease interrelated (Diabetes, the 37th volume, the 1595th page (1988)).
In order to prevent or treat medicated porridge sample arteriosclerosis, constantly carried out suppressing the trial of various risk factors such as hyperlipemia, hypertension or insulin resistance up to now.But, though HMG-CoA reductase inhibitors such as known pravastatin can improve hyperlipemia, the result brings into play the arteriosclerotic inhibition effect of medicated porridge sample, but for serious hyperlipemia or arteriosclerotic, the not talkative very abundant (Biochim.Biophys.Acta of the effect of single medicine, the 960th volume, the 294th page (1988)).Therefore, the medicine and the therapy that also need more novel effect.
In addition, for hyperlipemia and arteriosclerosis, known is effective (The Washington Manual of MedicalTherapeutics with the medication combined medication that has effect for reducing fat more than 2 kinds, the 29th edition, Department of Medicine, WashingtonUniversity School of Medicine (1998)).In addition, also pointed out the lipid lowerers of novel action mechanism and the effectiveness (Diabete﹠amp of existing medication combined medication; Metabolisme (Paris), the 21st volume, the 139th page (nineteen ninety-five)).The pharmaceutical composition of 6-two (1-Methylethyl) phenyl ((2,4,6-three (1-Methylethyl) phenyl) acetyl group) sulfamate and atorvastatin drug combination is for example specifically disclosed in the WO97/16184 communique 2.
But which kind of medicine and the combination of HMG-CoA reductase inhibitor are effectively real, and can become safe lipid lowerers or arteriosclerotic preventive drug or curative, still have a lot of not clear parts.In addition, because strong (for example, the Drugs of the Future of the drug toxicity that has, the 25th volume, the 171st page (2000)), think avoid its toxicity with the drug combination Therapeutic Method of other medicines in very important, that is, think to the most important thing is to select which kind of medicine.
Disclosure of the Invention
The inventor etc. are in view of prevention and treat arteriosclerotic importance, various researchs have been carried out repeatedly, found that by uniting and use N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor, can improve effect for reducing fat, suppress effect for aortic arteriosclerotic development, morbidity for the vitiligoidea of falling ill at the extremities joint position suppresses effect, and a little less than the toxicity, therefore useful as the preventive drug or the curative (particularly curative) of arteriosclerosis or vitiligoidea (particularly arteriosclerosis), thus the present invention finished.
Therefore, the object of the present invention is to provide and a kind ofly be used for giving simultaneously or give N-(1-octyl group-5-carboxymethyl-4 blanking time respectively, 6-dimethyl indoline-7-yl)-2, the pharmaceutical composition of 2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor (being preferred for preventing or treating the pharmaceutical composition of arteriosclerosis or vitiligoidea).
In addition, another object of the present invention is to provide the method for a kind of prevention or treatment arteriosclerosis or vitiligoidea, comprise (1-octyl group-5-carboxymethyl-4 with N-, 6-dimethyl indoline-7-yl)-2, the pharmacologically effective dose of 2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor gives or gives respectively blanking time Homoiotherm (particularly people) simultaneously.
The effective ingredient of pharmaceutical composition of the present invention is N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor.
In pharmaceutical composition of the present invention, N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide is to be recorded in the chemical compound that has following structural formula among the embodiment 4 of WO97/12860 number (EP0866059, USP6063806).
The therapeutic agent that one of effective ingredient of pharmaceutical composition of the present invention HMG-CoA reductase inhibitor originally is used as hyperlipemia uses, derive from the natural materials of microorganism, include interior by its deutero-semi-synthetic material and complete synthesis chemical compound, for example can be (+)-(3R that the spy opens clear 57-2240 number (USP4346227) record, 5R)-3,5-dihydroxy-7-((1S, 2S, 6S, 8S, 8aR)-6-hydroxy-2-methyl-8-((S)-and 2-methylbutyryl oxygen base)-1,2,6,7,8,8a-six hydrogen-1-naphthyl) enanthic acid (is designated hereinafter simply as pravastatin, Pravastatin), the spy opens (+)-(1S, the 3R of clear 57-163374 number (USP4231938) record, 7S, 8S, 8aR)-1,2,3,7,8,8a-six hydrogen-3,7-dimethyl-8-(2-((2R, 4R)-and tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthyl (S)-2-Methyl Butyric Acid ester (is designated hereinafter simply as lovastatin, Lovastatin), the spy opens (+)-(1S, the 3R of clear 56-122375 number (USP4444784) record, 7S, 8S, 8aR)-1,2,3,7,8,8a-six hydrogen-3,7-dimethyl-8-(2-((2R, 4R)-and tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthyl 2,2-dimethyl butyrate acid esters (is designated hereinafter simply as simvastatin, Simvastatin), (±) (3R of clear 60-500015 number (USP4739073) record of special table
*, 5S
*6E)-7-(3-(4-fluorophenyl)-1-(1-Methylethyl)-1H-indole-2-yl)-3; 5-dihydroxy-6-heptenoic acid (is designated hereinafter simply as fluvastatin; Fluvastatin); (the 3R of Te Kaiping 1-216974 number (USP5006530) record; 5S; 6E)-7-(4-(4-fluorophenyl)-2; 6-two (1-Methylethyl)-5-methoxy pyridin-3-yl)-3; 5-dihydroxy-6-heptenoic acid (being designated hereinafter simply as Rivastatin); (the 3R of Te Kaiping 3-58967 number (USP5273995) record; 5S)-7-(2-(4-fluorophenyl)-5-(1-Methylethyl)-3-phenyl-4-phenyl amino carbonyl-1H-pyrroles-1-yl)-3; 5-dihydroxy enanthic acid (being designated hereinafter simply as Atorvastatin); (E)-3 of Te Kaiping 1-279866 number (USP5854259 and USP5856336) record; 5-dihydroxy-7-(4 '-(4 "-fluorophenyl)-2 '-cyclopropyl-quinoline-3 '-yl)-6-heptenoic acid (being designated hereinafter simply as Pitavastatin); perhaps the spy opens that (+) of flat 5-178841 number (USP5260440) record-(3R; 5S)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesyl amino) pyrimidine-5-yl)-3,5-dihydroxy-6 (E)-heptenoic acid (being designated hereinafter simply as Rosuvastatin) waits his spit of fland (statin) chemical compound.In addition, the effective ingredient HMG-CoA reductase inhibitor of pharmaceutical composition of the present invention also comprises disclosed other HMG-CoA reductase inhibitor in the communique of having put down in writing above-mentioned HMG-CoA reductase inhibitor.
As this HMG-CoA reductase inhibitor, preferred pravastatin, lovastatin, simvastatin, fluvastatin, Rivastatin, Atorvastatin, Rosuvastatin or Pitavastatin, more preferably pravastatin, lovastatin, simvastatin, fluvastatin, Atorvastatin, Rosuvastatin or Pitavastatin, more preferably pravastatin, Atorvastatin or Pitavastatin, further preferred pravastatin or Atorvastatin, preferred especially pravastatin.
It below is the planar structure formula of the representative substances of HMG-CoA reductase inhibitor.
The simvastatin fluvastatin
Rivastatin Atorvastatin
Rosuvastatin Pitava?statin
The effective ingredient N-of pharmaceutical composition of the present invention (1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide or HMG-CoA reductase inhibitor can be made salt according to conventional method as required.For example, can at room temperature handle 5 minutes to 30 minutes with corresponding acid by in solvent (for example can be ethers, esters or alcohols, preferred ethers), filter and collect the crystal of separating out, perhaps distillation obtains except that desolvating under reduced pressure.As this salt, inorganic acid salts such as hydrofluoride, hydrochlorate, hydrobromate, hydriodate, nitrate, perchlorate, sulfate or phosphate for example; Sulfonate such as mesylate, fluoroform sulphonate, esilate, benzene sulfonate or tosilate; Carboxylates such as fumarate, succinate, citrate, tartrate, oxalates or maleate; Perhaps amino acid salts such as glutamate, Glu or aspartate.
In addition, the effective ingredient N-of pharmaceutical composition of the present invention (1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide or HMG-CoA reductase inhibitor can be handled according to conventional method and alkali as required, thereby make corresponding officinal salt respectively.For example, can at room temperature handle 5 minutes to 30 minutes with corresponding alkali by in solvent (for example can be ethers, esters or alcohols, preferred ethers), filter and collect the crystal of separating out, perhaps distillation obtains except that desolvating under reduced pressure.As this salt, for example can be slaines such as alkali metal salts such as sodium salt, potassium salt, lithium salts, alkali salts such as calcium salt, magnesium salt, aluminum salt, iron salt, zinc salt, mantoquita, nickel salt, cobalt salt; Inorganic salts such as ammonium salt, t-octanylamine salt .alpha.-aminodiphenylmethane. salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucosamine salt, guanidinesalt, diethyl amine salt, triethylamine salt, hexanamine salt, N, organic salts such as amine salt such as N '-benzhydryl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl phenethylamine salt, piperazine salt, tetramethyl ammonium, three (methylol) aminomethane salt, preferred as alkali salt (particularly sodium salt or calcium salt).
In addition, in the effective ingredient HMG-CoA reductase inhibitor of pharmaceutical composition of the present invention, pravastatin, lovastatin, simvastatin, fluvastatin, Rivastatin, Atorvastatin or Pitavastatin comprise its lactone closed loop body or its officinal salt (particular certain cancers or calcium salt etc.).
The effective ingredient N-of pharmaceutical composition of the present invention (1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2, there are various geometric isomers in 2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor, perhaps have stereoisomer in the occasion that contains chiral carbon, various isomers or these mixture of isomers include in the present invention.
The effective ingredient N-of pharmaceutical composition of the present invention (1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor can be used as various hydrates and exist, and the mixture of various hydrates or these hydrates includes in the present invention.
In the present invention, " simultaneously " administration is so long as can get final product in the administration form of much at one time administration, and not special the qualification is preferably as single compositions administration.
In the present invention, " blanking time respectively " administration is so long as can get final product in the administration form of different time difference administrations, not special the qualification, for example at first give N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide or its officinal salt, then after the time of determining, give HMG-CoA reductase inhibitor, perhaps at first give the HMG-CoA reductase inhibitor, then after the time of determining, give N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide or its officinal salt.
In pharmaceutical composition of the present invention, preference such as following pharmaceutical composition,
(1) the HMG-CoA reductase inhibitor is the pharmaceutical composition of pravastatin, lovastatin, simvastatin, fluvastatin, Rivastatin, Atorvastatin, Rosuvastatin or Pitavastatin,
(2) the HMG-CoA reductase inhibitor is the pharmaceutical composition of pravastatin, lovastatin, simvastatin, fluvastatin, Atorvastatin, Rosuvastatin or Pitavastatin,
(3) the HMG-CoA reductase inhibitor is the pharmaceutical composition of pravastatin, Atorvastatin or Pitavastatin,
(4) the HMG-CoA reductase inhibitor is the pharmaceutical composition of pravastatin or Atorvastatin,
(5) the HMG-CoA reductase inhibitor is the pharmaceutical composition of pravastatin,
(6) the HMG-CoA reductase inhibitor is the pharmaceutical composition of Atorvastatin, more preferably for example following pharmaceutical composition,
(7) be used for giving simultaneously or give N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2 blanking time respectively, the pharmaceutical composition of 2-dimethyl propylene amide sulfate and HMG-CoA reductase inhibitor,
(8) as (7) described pharmaceutical composition, the HMG-CoA reductase inhibitor is pravastatin, lovastatin, simvastatin, fluvastatin, Rivastatin, Atorvastatin, Rosuvastatin or Pitavastatin,
(9) as (7) described pharmaceutical composition, the HMG-CoA reductase inhibitor is pravastatin, lovastatin, simvastatin, fluvastatin, Atorvastatin, Rosuvastatin or Pitavastatin,
(10) as (7) described pharmaceutical composition, the HMG-CoA reductase inhibitor is pravastatin, Atorvastatin or Pitavastatin,
(11) as (7) described pharmaceutical composition, the HMG-CoA reductase inhibitor is pravastatin or Atorvastatin,
Particularly preferred example such as following pharmaceutical composition,
(12) as (7) described pharmaceutical composition, be used for giving simultaneously or give N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2 blanking time respectively, 2-dimethyl propylene amide sulfate and Atorvastatin,
(13), be used for giving simultaneously or give N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide sulfate and pravastatin blanking time respectively as (7) described pharmaceutical composition.
The invention effect
Of the present inventionly be used for giving simultaneously or give N-(1-octyl group-5-carboxymethyl-4 blanking time respectively, 6-dimethyl indoline-7-yl)-2, the pharmaceutical composition of 2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor, for aortic arteriosclerosis, have good development and suppress effect, for vitiligoidea in the morbidity of extremities joint position, have good morbidity and suppress effect, therefore and a little less than the toxicity, as useful at the preventive drug or the curative (particularly curative) of the arteriosclerosis of Homoiotherm (particularly people) or vitiligoidea (particularly arteriosclerosis).
Industrial applicibility
The effective ingredient N-of pharmaceutical composition of the present invention (1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide or its officinal salt can easily prepare according to the method for W097/12860 (EP0866059, USP6063806) record.
In addition, the effective ingredient HMG-CoA reductase inhibitor of pharmaceutical composition of the present invention can be opened clear 57-2240 number (USP4346227), spy according to the spy and opens clear 57-163374 number (USP4231938), spy and open clear 56-122375 number (USP4444784), special table clear 60-500015 number (USP4739073), spy and open flat 1-216974 number (USP5006530), spy and open flat 3-58967 number (USP5273995), spy and open the method that flat 1-279866 number (USP5854259 and USP5856336) or spy open flat 5-178841 number (USP5260440) record and easily prepare.
Of the present inventionly be used for giving simultaneously or give N-(1-octyl group-5-carboxymethyl-4 blanking time respectively, 6-dimethyl indoline-7-yl)-2, the pharmaceutical composition of 2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor, has good effect for reducing fat, in addition, for aortic arteriosclerosis, have good development and suppress effect, for vitiligoidea in the morbidity of extremities joint position, have good morbidity and suppress effect, and it is a little less than the toxicity, therefore useful as the preventive drug or the curative (particularly curative) of arteriosclerosis or vitiligoidea (particularly arteriosclerosis).In addition, N-of the present invention (1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor are used in combination, and compare with individually dosed respectively occasion, show good effect.
The effective ingredient N-of pharmaceutical composition of the present invention (1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor can be mixed with unit administration form separately respectively separately, perhaps are blended in and physically are mixed with 1 unit administration form.
When using pharmaceutical composition of the present invention as the preventive drug of above-mentioned disease or curative, can be with effective ingredient N-(the 1-octyl group-5-carboxymethyl-4 of pharmaceutical composition of the present invention, 6-dimethyl indoline-7-yl)-2, both are own for 2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor, perhaps mix with the last excipient that allows of suitable pharmacology, diluent etc., as oral administrations such as tablet, capsule, granule, powder or syrups, perhaps as non-oral administrations such as injection or suppositorys.
These preparations can use excipient (sugar derivativess such as lactose, sucrose, glucose, mannitol, sorbitol for example; Starch derivatives such as corn starch, potato starch, α starch, dextrin; Cellulose derivatives such as crystalline cellulose; Arabic gum; Glucosan; The organic excipients such as enzyme polysaccharide of growing sturdily; And silicate derivative such as light silicon anhydride, synthetic aluminium silicate, calcium silicates, metasilicic acid magnesium aluminate; Phosphate such as calcium hydrogen phosphate; Carbonate such as calcium carbonate; Inorganic excipients such as sulfate such as calcium sulfate), lubricant (Metallic stearates such as stearic acid, calcium stearate, magnesium stearate for example; Talcum; Colloidal silica; Wax such as Cera Flava, spermaceti class; Boric acid; Adipic acid; Sulfate such as sodium sulfate; Ethylene glycol; Fumaric acid; Sodium benzoate; The DL leucine; Lauryl sulfate such as sodium lauryl sulfate, lauryl magnesium sulfate; Silicic acid such as silicic acid anhydride, hydrate of silicic acid class; And above-mentioned starch derivatives), binding agent (for example hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, Polyethylene Glycol and the chemical compound same), disintegrating agent (cellulose derivatives such as low degree of substitution hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethylcellulose calcium, internal crosslinking sodium carboxymethyl cellulose for example with above-mentioned excipient; Starch, the cellulose family of chemical modifications such as carboxymethyl starch, carboxymethyl starch sodium, crospolyvinylpyrrolidone), emulsifying agent (colloidal clay such as bentonite, propolis for example; Metal hydroxides such as magnesium hydroxide, aluminium hydroxide; Anion surfactant such as sodium lauryl sulfate, calcium stearate; Cationic surfactants such as benzalkonium chloride; And non-ionic surface active agent such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester), stabilizing agent (parabenses such as methyl parahydroxybenzoate, propyl p-hydroxybenzoate; Alcohols such as methaform, benzyl alcohol, phenethanol; Benzalkonium chloride; Phenols such as phenol, cresol; Thimerosal; Dehydroacetic acid; And sorbic acid), additives such as correctives (for example normally used sweeting agent, acidic flavoring agent, spice etc.), diluent, according to well-known method preparation.
The effective ingredient N-of pharmaceutical composition of the present invention (1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2, the dosage of 2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor and administration ratio can be according to various condition changings such as the activity of each medicine, patient's symptom, age, body weight.
Its dosage is according to differences such as symptom, ages, can 1 time to 6 times on the 1st for the adult, according to symptom while or the blanking time of administration respectively, during oral administration, be respectively each lower limit 0.1mg (preferred 0.5mg), upper limit 1000mg (preferred 500mg), during non-oral administration, be respectively each lower limit 0.01mg (preferred 0.05mg), upper limit 100mg (preferred 50mg).
In addition, the HMG-CoA reductase inhibitor with as original purposes--the consumption of-hyperlipidemia agent is compared, prevent or treat the occasion of arteriosclerotic purposes among the present invention, its consumption can reduce, in addition, since with N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2, the excellent results that 2-dimethyl propylene amide or its officinal salt coupling produce, dosage can further reduce.
In addition, the effective ingredient N-of pharmaceutical composition of the present invention (1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2, the dosage ratio of 2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor also can change significantly, N-(1-octyl group-5-carboxymethyl-4 for example, 6-dimethyl indoline-7-yl)-2, the dosage ratio of 2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor, by weight, can be in 1: 500 to 500: 1 scope, preferred 1: 100 to 100: 1, more preferably 1: 10 to 10: 1, most preferably 1: 5 to 5: 1.
N-(1-octyl group-5-carboxymethyl-4 particularly, 6-dimethyl indoline-7-yl)-2, the dosage ratio of 2-dimethyl propylene amide sulfate and pravastatin, by weight, be preferably 1: 2.5 to 2.5: 1, N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2, the dosage ratio of 2-dimethyl propylene amide sulfate and Atorvastatin by weight, is preferably 1: 2.5 to 5: 1.
The preferred forms of invention
Below, exemplify embodiment and formulation example illustrates in greater detail the present invention, but scope of the present invention is not limited to this.
Embodiment 1
Effect for reducing fat
The male F1b hamster in 11 ages in week is used in experiment.Animal is raised in metal cage, makes it freely to absorb the feedstuff and the water that contain 0.05% cholesterol and 10% Oleum Cocois.Medicine is as the suspension in 5% gumwater, and 1 time on the 1st, oral administration 7 days.After the final administration jejunitas 17 hours, under anesthesia, gather blood.Adopt the enzymatic assays serum lipids.The result is as shown in table 1.In addition, VLDL represents very low density lipoprotein (VLDL) in the table, and LDL represents low density lipoprotein, LDL, and HDL represents high density lipoprotein, and compd A is represented N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide sulfate.[table 1]
Cholesterol concentration activates the arteries and veins gruel type
TC VLDL+LDL HDL index contrasts 253.0 189.4 63.6 3.0 pravastatins, (3mg/kg) 244.0 170.6 73.3 2.3 compd As, (30mg/kg) 170.9 109.0 62.0 1.8 compd As+pravastatin 151.1 86.9 64.2 1.4, (30mg/kg)+, (3mg/kg)
Individually dosed group and N-(1-octyl group-5-carboxymethyl-4 of pravastatin, 6-dimethyl indoline-7-yl)-2, individually dosed group of 2-dimethyl propylene amide sulfate makes serum total cholesterol and serum VLDL+LDL cholesterol reduce respectively, but with two kinds of drug combinations, its effect further improves.In addition, for the index that develops into arteriosclerotic complexity---actuating arteries and veins gruel type index (VLDL+LDL cholesterol/HDL cholesterol), individually dosed group and N-(1-octyl group-5-carboxymethyl-4 of pravastatin, 6-dimethyl indoline-7-yl)-2, individually dosed group of 2-dimethyl propylene amide sulfate also makes this value reduce respectively, but with two kinds of drug combinations, its effect further improves.
Embodiment 2
Effect for the arteriosclerotic lesion development of high cholesterol diet load rabbit
The male New Zealand rabbit (Beishan Mountain Labes Co., Ltd., Japan) of raising body weight 1.0～1.5kg with the feedstuff that contains 0.5% cholesterol, 3% Oleum Arachidis hypogaeae semen and 3% Oleum Cocois (RC-4, Oriental yeast industry Co., Ltd., Japan) added up to for 10 weeks.The picked-up of limiting feed, per 1 of the forage volume that gives is 40g in 2 initial weeks, and 4 weeks of following are 50g, and last 4 weeks are 60g.Load carries out surgical operation after 2 weeks of beginning, and the nylon yarn in that the arteria saphena of right thigh portion is sterilized near the insertion diaphragm causes chronic endothelial injury in right thigh tremulous pulse to abdominal aorta.Nylon yarn is in fixing, as to remain on position state in 8 weeks of duration of test.Serves as that animal is divided into groups on the basis in high cholesterol diet load 2 all backs with the T-CHOL value.After above-mentioned operation, with HMG-CoA reductase inhibitor and ACAT inhibitor individually dosed or 8 weeks of administering drug combinations of difference.
(i) arteriosclerotic lesion area
Resolve in order to carry out morphology, the right thigh tremulous pulse of having implemented operation is photographed with the digital camera (trade (brand) name: Coolpix 900, Canon Co., Ltd.) that connects on computers.Use (the trade (brand) name: Adobe Photoshop 5.0 of Photo-retouch software, AdobeSystems company) and NIH Imaging software (ProductName: Scionimage 1.61cMacOs, Scion company) calculates the arteriosclerotic lesion area ratio long-pending, estimate aortic arteriosclerosis degree with respect to the large artery trunks surface of internal cavity.
(ii) extracellular lipid
Intravenous injection pentobarbital sodium (25mg/kg) uses the normal saline perfusion with rabbit anesthesia under the certain pressure of 100mmHg.Behind the perfusion, large artery trunks is extractd, photographed.For the right thigh tremulous pulse, carry out the pathological changes of the cross-section section of large artery trunks and resolve.With Met hanol Carnoy fixative that the right thigh tremulous pulse is fixing more than at least 24 hours.With a corpse or other object for laboratory examination and chemical testing with paraffin embedding after, make the section of each 5 μ m.For 1 corpse or other object for laboratory examination and chemical testing, cut off at 4 positions with the interval of 80 μ m, for each section, each makes 5 serial section.Use 1 in each serial section, carry out Elastica-Masson dyeing.Use is connected the digital camera (ProductName: Fujix CCD camera system HC-2500, description Film Co., Ltd. of Fuji) on the Leica system microscope, with 2.5 multiplying powers each section is photographed.For the variation of the matter of studying diseased region, use Adobe Photoshop 5.0, the area of each constituent is extracted.Carried out in the painted section of Elastica-Masson, will dye absinthe-green zone definitions is extracellular matrix (ECM), and the extracellular cavity or the space of white portion is defined as extracellular lipid (ECD).Use Adobe Photoshop 5.0 and Scion image 1.61c MacOs, measure the white portion area in each diseased region of cutting into slices, calculate meansigma methods.
The result is as shown in table 2.Compd A in the table is represented N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide sulfate.
[table 2]
Arteriosclerotic lesion area extracellular lipid (mm
2)
Rate (%) contrast 57.4 15.5 pravastatins (10mg/kg) 58.3 16.6 compd As (5mg/kg) 45.8 10.7 compd As+pravastatin 40.9 3.0 (5mg/kg)+(10mg/kg)
Can confirm that by The above results a kind of medicine of compd A can reduce the arteriosclerotic lesion area and the extracellular lipid of thigh tremulous pulse, and the not effect of a kind of medicine of pravastatin gives two kinds of medicines by uniting, its effect is collaborative to be strengthened.
Formulation example 1
Tablet
With sodium salt of pravastatin (10.0mg), N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide sulfate (30.0mg), lactose (408.0mg), corn starch (50.0mg) and magnesium stearate (2.0mg) are mixed, use the tablet machine tabletting, make the tablet of 1 500mg.This tablet can be implemented coating (preferred sugar-coat) as required.
Claims (14)
1, a kind of pharmaceutical composition is used for giving simultaneously or gives N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide or its officinal salt and HMG-CoA reductase inhibitor blanking time respectively.
2, pharmaceutical composition as claimed in claim 1, HMG-CoA reductase inhibitor are pravastatin, lovastatin, simvastatin, fluvastatin, Rivas tat in, Atorvastatin, Rosuvastatin or Pitavastatin.
3, pharmaceutical composition as claimed in claim 1, HMG-CoA reductase inhibitor are pravastatin, lovastatin, simvastatin, fluvastatin, Atorvastatin, Rosuvastatin or Pitavastatin.
4, pharmaceutical composition as claimed in claim 1, HMG-CoA reductase inhibitor are pravastatin, Atorvastatin or Pitavastatin.
5, pharmaceutical composition as claimed in claim 1, HMG-CoA reductase inhibitor are pravastatin or Atorvastatin.
6, pharmaceutical composition as claimed in claim 1, HMG-CoA reductase inhibitor are pravastatin.
7, pharmaceutical composition as claimed in claim 1, HMG-CoA reductase inhibitor are Atorvastatin.
8, a kind of pharmaceutical composition is used for giving simultaneously or gives N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide sulfate and HMG-CoA reductase inhibitor blanking time respectively.
9, pharmaceutical composition as claimed in claim 8, HMG-CoA reductase inhibitor are pravastatin, lovastatin, simvastatin, fluvastatin, Rivastatin, Atorvastatin, Rosuvastatin or Pitavastatin.
10, pharmaceutical composition as claimed in claim 8, HMG-CoA reductase inhibitor are pravastatin, lovastatin, simvastatin, fluvastatin, Atorvastatin, Rosuvastatin or Pitavastatin.
11, pharmaceutical composition as claimed in claim 8, HMG-CoA reductase inhibitor are pravastatin, Atorvastatin or Pitavastatin.
12, pharmaceutical composition as claimed in claim 8, HMG-CoA reductase inhibitor are pravastatin or Atorvastatin.
13, pharmaceutical composition as claimed in claim 8 is used for giving simultaneously or gives N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide sulfate and Atorvastatin blanking time respectively.
14, pharmaceutical composition as claimed in claim 8 is used for giving simultaneously or gives N-(1-octyl group-5-carboxymethyl-4,6-dimethyl indoline-7-yl)-2,2-dimethyl propylene amide sulfate and pravastatin blanking time respectively.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000265082 | 2000-09-01 | ||
| JP265082/2000 | 2000-09-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1473042A true CN1473042A (en) | 2004-02-04 |
Family
ID=18752403
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA018184723A Pending CN1473042A (en) | 2000-09-01 | 2001-08-29 | Medical compositions |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP1314423A4 (en) |
| KR (1) | KR20030029871A (en) |
| CN (1) | CN1473042A (en) |
| AU (2) | AU8254101A (en) |
| BR (1) | BR0113523A (en) |
| CA (1) | CA2420951A1 (en) |
| CZ (1) | CZ2003593A3 (en) |
| HU (1) | HUP0301728A3 (en) |
| IL (1) | IL154414A0 (en) |
| MX (1) | MXPA03001857A (en) |
| NO (1) | NO20030946L (en) |
| NZ (1) | NZ524406A (en) |
| PL (1) | PL362244A1 (en) |
| RU (1) | RU2246302C2 (en) |
| SK (1) | SK2552003A3 (en) |
| WO (1) | WO2002020009A1 (en) |
| ZA (1) | ZA200301543B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0301728A3 (en) * | 2000-09-01 | 2004-05-28 | Sankyo Co | Hmg-coa reductase inhibiting pharmaceutical compositions and their use |
| AU2004267972B2 (en) | 2003-08-29 | 2010-07-08 | Kowa Co., Ltd. | Method of stabilizing lipid-rich plaque and method of preventing rupture thereof |
| TW200619204A (en) * | 2004-12-10 | 2006-06-16 | Kowa Co | Method for reduction, stabilization and prevention of rupture of lipid rich plaque |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3720395B2 (en) * | 1994-09-20 | 2005-11-24 | 京都薬品工業株式会社 | Novel heterocyclic derivative, production method thereof and pharmaceutical use thereof |
| DK0866059T3 (en) * | 1995-10-05 | 2002-03-25 | Kyoto Pharma Ind | New heterocyclic derivatives and their medical use |
| BR9611410A (en) * | 1995-11-02 | 1999-01-05 | Warner Lambert Co | Pharmaceutical method and composition to regulate the concentration of lipids |
| EP0944602A1 (en) * | 1996-11-27 | 1999-09-29 | Pfizer Inc. | Apo b-secretion/mtp inhibitory amides |
| CA2307553C (en) * | 1997-10-28 | 2003-06-17 | Korea Institute Of Science And Technology | Citrus peel extract as inhibitor of acyl coa-cholesterol-o-acyltransferase, inhibitor of macrophage-lipid complex accumulation on the arterial wall and preventive or treating agent for hepatic diseases |
| TR200100205T2 (en) * | 1998-07-21 | 2001-05-21 | Warner-Lambert Company | Co-administration of ACAT and MMP inhibitors for the treatment of atherosclerotic lesions. |
| AU7717500A (en) * | 1999-09-30 | 2001-04-30 | Merck & Co., Inc. | Anti-hypercholesterolemic drug combination |
| HUP0301728A3 (en) * | 2000-09-01 | 2004-05-28 | Sankyo Co | Hmg-coa reductase inhibiting pharmaceutical compositions and their use |
-
2001
- 2001-08-29 HU HU0301728A patent/HUP0301728A3/en unknown
- 2001-08-29 CN CNA018184723A patent/CN1473042A/en active Pending
- 2001-08-29 SK SK255-2003A patent/SK2552003A3/en not_active Application Discontinuation
- 2001-08-29 RU RU2003105835/15A patent/RU2246302C2/en not_active IP Right Cessation
- 2001-08-29 AU AU8254101A patent/AU8254101A/en active Pending
- 2001-08-29 EP EP01961177A patent/EP1314423A4/en not_active Withdrawn
- 2001-08-29 AU AU2001282541A patent/AU2001282541B2/en not_active Ceased
- 2001-08-29 PL PL01362244A patent/PL362244A1/en unknown
- 2001-08-29 CZ CZ2003593A patent/CZ2003593A3/en unknown
- 2001-08-29 NZ NZ524406A patent/NZ524406A/en unknown
- 2001-08-29 BR BR0113523-6A patent/BR0113523A/en not_active IP Right Cessation
- 2001-08-29 KR KR10-2003-7002861A patent/KR20030029871A/en not_active Application Discontinuation
- 2001-08-29 IL IL15441401A patent/IL154414A0/en unknown
- 2001-08-29 WO PCT/JP2001/007438 patent/WO2002020009A1/en not_active Application Discontinuation
- 2001-08-29 CA CA002420951A patent/CA2420951A1/en not_active Abandoned
- 2001-08-29 MX MXPA03001857A patent/MXPA03001857A/en unknown
-
2003
- 2003-02-25 ZA ZA200301543A patent/ZA200301543B/en unknown
- 2003-02-28 NO NO20030946A patent/NO20030946L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU2001282541B2 (en) | 2004-06-24 |
| SK2552003A3 (en) | 2003-08-05 |
| CA2420951A1 (en) | 2003-02-28 |
| ZA200301543B (en) | 2004-06-09 |
| NZ524406A (en) | 2004-06-25 |
| MXPA03001857A (en) | 2003-06-04 |
| BR0113523A (en) | 2004-06-29 |
| PL362244A1 (en) | 2004-10-18 |
| KR20030029871A (en) | 2003-04-16 |
| HUP0301728A2 (en) | 2003-08-28 |
| NO20030946D0 (en) | 2003-02-28 |
| NO20030946L (en) | 2003-04-08 |
| AU8254101A (en) | 2002-03-22 |
| CZ2003593A3 (en) | 2003-05-14 |
| WO2002020009A1 (en) | 2002-03-14 |
| IL154414A0 (en) | 2003-09-17 |
| RU2246302C2 (en) | 2005-02-20 |
| EP1314423A4 (en) | 2004-05-19 |
| HUP0301728A3 (en) | 2004-05-28 |
| EP1314423A1 (en) | 2003-05-28 |
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| AD01 | Patent right deemed abandoned | ||
| C20 | Patent right or utility model deemed to be abandoned or is abandoned |